Human bones are subject to a continuous dynamic process of reconstruction which involves bone reabsorption and bone synthesis. These processes are controlled by cell types which are specialised for this purpose. Bone synthesis is based on the deposition of bone matrix by osteoblasts, while bone reabsorption is based on the breakdown of bone matrix by osteoclasts. The majority of bone diseases are due to the balance between bone formation and bone reabsorption being disturbed. Osteoporosis is characterised by a loss of bone matrix. Activated osteoclasts are multinuclear cells, having a diameter of up to 400 .mu.m which demolish bone matrix. Activated osteoclasts attach themselves to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called sealing zone, the region between their cell membrane and the bone matrix. The acid environment and the proteases bring about the breakdown of the bone.
Studies have demonstrated that the attachment of osteoclasts to the bones is regulated by integrin receptors on the cell surface of osteoclasts.
Integrins are a superfamily of receptors which includes, inter alia, the fibrinogen receptor .alpha..sub.IIb.beta..sub.3 on the blood platelets and the vitronectin receptor .alpha..sub.V.beta..sub.3. The vitronectin receptor, .alpha..sub.V.beta..sub.3, is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the smooth blood vessel musculature, osteoclasts and tumor cells. The .alpha..sub.V.beta..sub.3 vitronectin receptor which is expressed on the osteoclast membrane regulates the process of attachment to the bones and of bone reabsorption and consequently contributes to osteoporosis.
In this context, .alpha..sub.V.beta..sub.3 binds to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor antibody (23C6) which inhibit tooth breakdown by osteoclasts and the migration of osteoclasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. report that echistatin, an RGD peptide from snake venom, is a potent inhibitor of bone reabsorption in a tissue culture and an inhibitor of the attachment of osteoclasts to bones. Fischer et al. (Endocrinology, 1993, 132, 1411) were able to demonstrate that, in the rat, echistatin also inhibits bone reabsorption in vivo.
The .alpha..sub.V.beta..sub.3 vitronectin receptor on human cells of the smooth blood vessel musculature of the aorta stimulates migration of these cells into the neointima, a process which finally leads to arteriosclerosis and restenosis following angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).
Brooks et al. (Cell 1994, 79, 1157) have demonstrated that antibodies against .alpha..sub.V.beta..sub.3 or .alpha..sub.V.beta..sub.3 antagonists are able to shrink tumors by inducing the apoptosis of blood vessel cells during angiogenesis. Chersh et al. (Science 1995, 270, 1500) describe anti-.alpha..sub.V.beta..sub.3 antibodies or .alpha..sub.V.beta..sub.3 antagonists which inhibit bFGF-induced angiogenesis processes in the rat eye, something which might be of therapeutic value in the treatment of retinopathies.
EP-A 449 079, EP-A 530 505, EP-A 566 919 and WO 93/18057 describe hydantoin derivatives, and WO 95/14008 describes substituted 5-membered ring heterocycles, both of which sets of compounds exhibit thrombocyte aggregation-inhibiting effects. Patent Application WO 94/12181 describes substituted aromatic or non-aromatic ring systems, and WO 94/08577 describes substituted heterocycles, both of which sets of compounds act as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528 586 and EP-A-528 587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710 describes aryl derivatives, all of which sets of compounds act as inhibitors of bone reabsorption by osteoclasts. WO 95/28426 describes RGD peptides which act as inhibitors of bone reabsorption, angiogenesis and restenosis. WO 96/00574 describes benzodiazepines, and WO 96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a 5-membered ring carrying a nitrogen, both of which sets of compounds act as vitronectin receptor antagonists.